2-oxo-1-pyrrolidine derivatives, process for preparing them...

Details 2-oxo-1-pyrrolidine derivatives, process for preparing them... 2-oxo-1-pyrrolidine derivatives, process for preparing them...

2002-08-20

2004-03-30

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06713635

ABSTRACT:

The invention concerns 2-oxo-1-pyrrolidine derivatives and a process for preparing them and their uses. The invention also concerns a process for preparing &agr;-ethyl-2-oxo-1-pyrrolidine acetamide derivatives from unsaturated 2-oxo-1-pyrrolidine derivatives.
Particularly the invention concerns novel intermediates and their use in methods for the preparation of (S)-(−)-&agr;-ethyl-2-oxo-1-pyrrolidine acetamide, which is referred under the International Nonproprietary Name of Levetiracetam, its dextrorotatory enantiomer and related compounds. Levetiracetam is shown as having the following structure:
Levetiracetam, a laevorotary compound is disclosed as a protective agent for the treatment and the prevention of hypoxic and ischemic type aggressions of the central nervous system in the European patent No. 162036. This compound is also effective in the treatment of epilepsy, a therapeutic indication for which it has been demonstrated that its dextrorotatory enantiomer (R)-(+)-&agr;-ethyl-2-oxo-1-pyrrolidine acetamide completely lacks activity (A. J. GOWER et al., Eur. J. Pharmacol., 222, (1992), 193-203). Finally, in the European patent application No. 0 645 139 this compound has been disclosed for its axiolytic activity.
The asymmetric carbon atom carries a hydrogen atom (not shown) positioned above the plane of the paper. The preparation of Levetiracetam has been described in the European patent No. 0162 036 and in the British patent No. 2 225 322, both of which are assigned to the assignee of the present invention. The preparation of the dextrorotatory enantiomer (R)-(+)-&agr;-ethyl-2-oxo-1-pyrrolidine acetamide has been described in the European patent No. 0165 919. Nevertheless, these approaches do not fully satisfy the requirements for an industrial process. Therefore, a new approach has been developed via the asymmetric hydrogenation of new precursors.
In one aspect, the invention provides a compound having the general formula (A) and pharmaceutically acceptable salts thereof,
wherein X is —CONR
5
R
6
or —COOR
7
or —COR
8
or CN;
R
1
is hydrogen or alkyl, aryl, heterocycloalkyl, heteroaryl, halogen, hydroxy, amino, nitro, cyano;
R
2
, R
3
, R
4
, are the same or different and each is independently hydrogen or halogen, hydroxy, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amido, sulfonic acid, sulfonamide, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, alkylsulfinyl, arylsulfmyl, alkylthio, arylthio, alkyl, alkoxy, oxyester, oxyamido, aryl, arylamino, axyloxy, heterocycloalkyl, heteroaryl, vinyl;
R
5
, R
6
, R
7
are the same or different and each is independently hydrogen, hydroxy, alkyl, aryl, heterocycloalkyl, heteroaryl, alkoxy, aryloxy; and
R
8
is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycloalkyl, heteroaryl, alkylthio, arylthio.
The term alkyl as used herein, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof and contains 1-20 carbon atoms, preferably 1-5 carbon atoms. The alkyl group may optionally be substituted by 1 to 5 substituents independently selected from the group consisting halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amido, sulfonic acid, sulfonamide, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, oxyester, oxyamido, heterocycloalkyl, heteroaryl, vinyl, (C1-C5)alkoxy, (C6-C10)aryloxy, (C6-C10)aryl. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least a group selected from halogen, hydroxy, thiol, amino, nitro, cyano, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.
The term “heterocycloalkyl”, as used herein, represents an “(C1-C6)cycloalkyl” as defined above, having at least one O, S and/or N atom interrupting the carbocyclic ring structure such as tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholino and pyrrolidinyl groups or the same substituted by at least a group selected from halogen, hydroxy, thiol, amino, nitro, cyano.
The term “alkoxy”, as used herein includes —O-alkyl groups wherein “alkyl” is defined above. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least a halo group such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl.
The term “alkylthio” as used herein, includes Bakyl groups wherein “alkyl” is defined above. Preferred alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least a halo group, such as trifluoromethyl, trichloromethyl, 2,2,2-trichloroethyl, 1,1-dimethyl-2,2-dibromoethyl, 1, 1-dimethyl-2,2,2-trichloroethyl.
The term “alkylamino” as used herein, includes —NHalkyl or —N(alkyl)
2
groups wherein “alkyl” is defined above. Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl, butyl, iso or ter-butyl, 2,2,2-trimethylethyl or the same substituted by at least a halo group.
The term “aryl” as used herein, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl, phenoxy, naphthyl, arylalkyl, benzyl, optionally substituted by 1 to 5 substituents independently selected from the group halogen, hydroxy, thiol, amino, nitro, cyano, acyl, acyloxy, sulfonyl, sulfinyl, alkylamino, carboxy, ester, ether, amido, sulfonic acid, sulfonamide, alkylsulfonyl, alkoxycarbonyl, alkylsulfinyl, alkylthio, oxyester, oxyamido, aryl, (C1-C6)alkoxy, (C6-C10)aryloxy and (C1-C6)alkyl. The aryl radical consists of 1-3 rings preferably one ring and contains 2-30 carbon atoms preferably 6-10 carbon atoms. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, naphthyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.
The term “arylanino” as used herein, includes —NHaryl or —N(aryl)
2
groups wherein “aryl” is defined above. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.
The term “aryloxy”, as used herein, includes —O-aryl groups wherein “aryl” is defined as above. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.
The term “arylthio”, as used herein, includes aryl groups wherein “aryl” is defined as above. Preferred aryl groups are, phenyl, halophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, benzyl, halobenzyl, cyanobenzyl, methoxybenzyl, nitrobenzyl, 2-phenylethyl.
The term “halogen”, as used herein, includes an atom of Cl, Br, F, I.
The term “hydroxy”, as used herein, represents a group of the formula —OH.
The term “thiol”, as used herein, represents a group of the formula —SH.
The teem “cyano”, as used herein, represents a group of the formula —CN.
The term “ritro”, as used herein, represents a group of the formula —NO
2
.
The term “amino”, as used herein, represents a group of the formula —NH
2
.
The term “carboxy”, as used herein, represents a group of the formula —COOH.
The term “sulfonic acid”, as used herein, represents a group of the formula —SO
3
H.
The term “sulfonamide”, as used herein, represents a group of the formula —SO
2
NH
2
.
The term “heteroaryl”, as used herein, unless otherwise indicated, represents an “aryl” as defined above, having at least one O, S and/or N interrupting the carbocyclic ring structure, such as pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyiimidyl, quinolyl, isoquinolyl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzthiazolyl, or benzoxazolyl, optionally substituted

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